Abstract Brain ischemia induced by cardiac arrest or stroke affects over one million people in the US every year, and can have devastating consequences. Ischemia-induced disability is major burden on families and healthcare systems. This problem will have an even greater impact as our population ages, because age is the key risk factor for cardiac arrest and ischemic stroke. Thus, there is an urgent need to define the role of age in outcome after brain ischemia/stroke in order to develop novel therapeutic strategies tailored for elderly ischemia/stroke patients. Ischemia is a severe form of metabolic stress that activates both pathological and protective path- ways. Outcome is improved when protective pathways dominate. The poor recovery of elderly patients after an ischemic event implies that aging is associated with a decline in the brain's capacity to activate pro-survival pathways after an ischemic episode. Indeed, activation of several pro-survival pathways is markedly impaired in aged brains. This is most evident in O-linked ?-N-acetylglucosamine (O-GlcNAc) modification of proteins, a post-translational modification and potent pro-survival pathway in a variety of stress conditions. While it is known that age is a key risk factor for poor outcome after brain ischemia/stroke and that activation of protective pathways improves outcome, we do not yet known how to apply this knowledge to improve outcome in aged patients who have suffered brain ischemia/stroke. Our long-term goal is to improve outcome in elderly patients after an ischemic event. The objective here is to determine why resistance to ischemic stress is decreased in aged brains, and to develop strategies to increase resistance. Our central hypothesis is that aging is associat- ed with a decline in the brain's capacity to activate protective pathways in response to stress conditions, and that boosting these pathways increases tolerance to stress. Based on results from ischemia experiments on aged animals, and using our new neuron-specific transgenic and knockout mouse models, we will test our hy- pothesis by pursuing the following specific aims: 1) Determine mechanisms underlying the age-related decline in the ability of the brain to activate O-GlcNAc modification upon transient forebrain ischemia and develop res- cue strategies; 2) Determine the extent to which boosting O-GlcNAc modification improves stroke outcome in aged brains. The proposed project is innovative because we will take a novel approach to neuroprotection that boosts an endogenous protective pathway, a substantial departure from current approaches that interfere with pathological pathways; we will focus on brain ischemia in aged animals; and importantly, this will the first study to investigate the O-GlcNAc pathway in brain ischemia/stroke. The proposed research is significant because we expect that this new approach to neuroprotection, specifically tailored to increase the resistance of aged brains to an ischemic challenge, will be a major breakthrough toward improving outcomes in elderly patients after an ischemic event.